The aim of this proposal is to expand the scope of a funded NIH project "A longitudinal MRI Study of Infants at Risk for Autism," (RO1 HD055741- IBIS network) through adding 3-D Proton Echo Planar Spectroscopic Imaging (3D PEPSI) to allow measurements of brain chemistry in 6 month-old siblings of children diagnosed with autism (high risk) and age-matched infants without a family history of autism (low risk) who then are rescanned at 12 months and clinically assessed at 12 and 24 months. Specifically, we plan to incorporate 3D PEPSI into our ongoing MRI/DTI structural imaging protocol (29 6 month high risk infants studied to date, 71 pending for the parent project total of 100 6mo studies), and scan additional infants (20 additional scans budgeted per year during the proposed 2-year project- for a total of 90 high-risk and 40 low-risk 6 month infants) to supplement target recruitment goals of the parent grant and repeat failed studies on another night. A secondary aim of this proposal is to develop automated 3D outer volume saturation band placement techniques and QC procedures for implementation of PEPSI technology at other sites involved in our imaging consortium, UNC- Chapel Hill, U Penn/ CHOP, Wash U, and Montreal Neurological Institute (DCC), to allow multi-site 3D PEPSI follow-up studies of this longitudinal cohort. Our funded project is investigating relationships between brain structural development and autism symptom onset that typically presents between 12 and 24 months of age. The proposed supplement will add complementary brain chemical information to assess mechanisms underlying hypothesized abnormalities of brain growth (regions, tissues, structures and fiber tracts) measured by MRI/ DTI and relationships to clinical features. 3D PEPSI, recently developed and implemented on our 3T Siemens TIM Trio scanner, provides highly resolved quantifiable chemical images with improved anatomical coverage and is particularly well suited for rapid scanning of infants during normal sleep. Our research team, in addition to being highly skilled at pediatric imaging studies, is at the forefront for developing and clinically applying chemical imaging techniques and has developed analytical tools specifically designed for highly efficient, reliable, and valid processing of 3D brain chemical data. These results will provide important insights into brain development, behavioral phenotypes and the underlying neurobiology of autism. PUBLIC HEALTH RELEVANCE: Research proposed in this grant targets challenges outlined by the Interagency Autism Coordinating Committee (IACC) Strategic Plan for Autism Spectrum Disorder (ASD) Research (January 2009). Specifically, the project will address heterogeneity in 6 month-old infants at high risk for ASD due to an older affected sibling, who are imaged longitudinally at 6, 12 and 24 months, then diagnosed at 24 months that is confirmed at age 3. Brain chemical measures collected as part of this project have the potential to help identify distinct clinical subtypes of ASD having specific prognostic and treatment implications. Brain chemical measurements will provide biomarkers that may identify distinct ASD endophenotypes, for example, infants potentially having subtle mitochondrial dysfunction, and help elucidate underlying pathophysiological mechanisms responsible for brain developmental abnormalities in autism.